Astrocytic aryl hydrocarbon receptor mediates chronic kidney disease‐associated mental disorders involving GLT1 hypofunction and neuronal activity enhancement in the mouse brain

Chronic kidney disease (CKD)‐associated mental disorders have been attributed to the excessive accumulation of hemodialysis‐resistant indoxyl‐3‐sulfate (I3S) in the brain. I3S not only induces oxidative stress but is also a potent endogenous agonist of the aryl hydrocarbon receptor (AhR). Here, we investigated the role of AhR in CKD‐induced brain disorders using a 5/6 nephrectomy‐induced CKD mouse model, which showed increased I3S concentration in both blood and brain, anxiety and impaired novelty recognition, and AhR activation in the anterior cortex. GFAP+ reactive astrocytes were increased accompanied with the reduction of glutamate transporter 1 (GLT1) on perineuronal astrocytic processes (PAPs) in the anterior cingulate cortex (ACC) in CKD mice, and these alterations were attenuated in both neural lineage‐specific and astrocyte‐specific Ahr conditional knockout mice (nAhrCKO and aAhrCKO). By using chronic I3S treatment in primary astrocytes and glia‐neuron (GN) mix cultures to mimic the CKD brain microenvironment, we also found significant reduction of GLT1 expression and activity in an AhR‐dependent manner. Chronic I3S treatment induced AhR‐dependent pro‐oxidant Nox1 and AhR‐independent anti‐oxidant HO‐1 expressions. Notably, AhR mediates chronic I3S‐induced neuronal activity enhancement and synaptotoxicity in GN mix, not neuron‐enriched cortical culture. In CKD mice, neuronal activity enhancement was observed in ACC and hippocampal CA1, and these responses were abrogated by both nAhrCKO and aAhrCKO. Finally, intranasal AhR antagonist CH‐223191 administration significantly ameliorated the GLT1/PAPs reduction, increase in c‐Fos+ neurons, and memory impairment in the CKD mice. Thus, astrocytic AhR plays a crucial role in the CKD‐induced disturbance of neuron‐astrocyte interaction and mental disorders. Main Points CKD elevates brain I3S to activate astrocytic AhR, which mediates astrogliosis with GLT1 hypofunction and enhances neuronal activity in ACC and hippocampus. Intranasal AhR antagonist administration ameliorates CKD‐induced brain/behavioral changes.